For the present reporting period, this project has been focused upon the potential mechanism(s) underlying the selective brain tumor (CNS) cell line cytotoxicity of certain quaternized ellipticine derivatives. One of these compounds, 9-methoxy-2methyl ellipticinium acetate (MNME) was equal to or greater than 10-fold more cytotoxic to 75% of tested tumor cell lines of CNS origin than to the vast majority (greater than 95%) of tested cell lines representing six other human tumor phenotypes (leukemia, lung, colon, melanoma, ovarian, renal). CNS cell lines responsive to MNME accumulated substantially more drug over a wide concentration range than did both CNS and non CNS cell lines refractory to MNME. MNME uptake by responsive CNS cell lines was mediated by a high affinity (apparent k(m) = 1.5 to 2.0 micromoles) transport system. Uptake was temperature dependent, sodium and pH independent, highly concentrative and inhibited by the amine transport inhibitor reserpine (apparent Ki = 0.5 to 1.0 micromoles). MNME uptake was inhibited by catecholamines (norepinephrine = dopamine >>epinephrine), the indoleamine, 5-HT (serotonin) , the polyamine, spermine, as well as by secondary and tertiary tricyclic amine antidepressant drugs. Studies with a series of ellipticinium and ellipticine analogs demonstrated a positive correlation between high-affinity (apparent Ki = apparent K(m) of MNME) interaction of these analogs with the amine transport system and selective cytotoxicity of CNS to CNS tumor lines.